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
 Arene (Ar-H) is the generic term for an aromatic hydrocarbon
 The aryl group (Ar) is derived by removal of a hydrogen atom from an arene
 Aromatic compounds undergo ELECTROPHILIC AROMATIC
SUBSTITUTION (EAS)
 The electrophile has a full or partial positive charge
2

 Benzene reacts with an electrophile using two of its
 electrons
 This first step is like an addition to an ordinary double bond
 Unlike an addition reaction, the benzene ring reacts further so that it may regenerate the very stable aromatic system
 In step 1 of the mechanism, the electrophile reacts with two
 electrons from the aromatic ring to form an arenium ion

In step 2 , a proton is removed and the aromatic system is regenerated
3
 The energy diagram of this reaction shows that the first step is highly endothermic and has a large

G ‡
(1)
 The first step requires the loss of aromaticity of the very stable benzene ring, which is highly unfavorable


The first step is rate-determining

The second step is highly exothermic and has a small

G ‡
(2)
The ring regains its aromatic stabilization, which is a highly favorable process
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
st

Halogenation of benzene requires the presence of a Lewis acid
 Fluorination occurs so rapidly it is hard to stop at monofluorination of the ring
 A special apparatus is used to perform this reaction
 Iodine is so unreactive that an alternative method must be used
5
MECHANISM: IMPORTANT
 In the step 1 of the mechanism, bromine reacts with ferric bromide to generate an electrophilic bromine species
 In step 2 , the highly electrophilic bromine reacts with
 electrons of the benzene ring, forming an arenium ion

In step 3 , a proton is removed from the arenium ion and aromaticity is regenerated
 The FeBr
3 catalyst is regenerated
6

nd

Nitration of benzene occurs with a mixture of concentrated nitric and sulfuric acids
 The electrophile for the reaction is the nitronium ion (NO
2
+ )

rd
 Sulfonation occurs most rapidly using fuming sulfuric acid
(concentrated sulfuric acid that contains SO
3
)
 The reaction also occurs in conc. sulfuric acid, which generates small quantities of
SO
3
, as shown in step 1 below
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 Sulfonation is an equilibrium reaction ; all steps involved are equilibria


The sulfonation product is favored by use of concentrated or fuming sulfuric acid
Desulfonation can be accomplished using dilute sulfuric acid (i.e. with a high concentration of water), or by passing steam through the reaction and collecting the volatile desulfonated compound as it distils with the steam

th
 An aromatic ring can be alkylated by an alkyl halide in the presence of a Lewis acid
 The Lewis acid serves to generate a carbocation electrophile
9 10
 Primary alkyl halides probably do not form discreet carbocations but the primary carbon in the complex develops considerable positive charge
 Any compound that can form a carbocation can be used to alkylate an aromatic ring

th
 An acyl group has a carbonyl attached to some R group
 Friedel-Crafts acylation requires reaction of an acid chloride or acid anhydride with a Lewis acid such as aluminium chloride
11 12
3

 Acid chlorides are made from carboxylic acids
(Will be studied in Chapter 17)
13
 The electrophile in Friedel-Crafts acylation is an acylium ion
 The acylium ion is stabilized by resonance
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14


In Friedel-Crafts alkylation, the alkyl carbocation intermediate may rearrange to a more stable carbocation prior to alkylation
 The reaction of n-butyl bromide leads to a mixture of products derived from primary and secondary carbocations

Powerful electron-withdrawing groups make an aromatic ring much less reactive toward Friedel-Crafts alkylation or acylation
 Amino groups also make the ring less reactive to Friedel-Crafts reaction because they become electron-withdrawing groups upon Lewis acid-base reaction with the
Lewis acid catalyst
15
 Aryl and vinyl halides cannot be used in Friedel-Crafts reactions because they do not form carbocations readily
 Polyalkylation occurs frequently with Friedel-Crafts alkylation because the first alkyl group introduced activates the ring toward further substitution
 Polyacylation does not occur because the acyl group deactivates the aromatic ring to further substitution
16
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
 Primary alkyl halides often yield rearranged products in Friedel-
Crafts alkylation which is a major limitation of this reaction
 Unbranched alkylbenzenes can be obtained in good yield by acylation followed by Clemmensen reduction
 Clemmensen reduction reduces phenyl ketones to the methylene (CH
2
) group
 This method can be used to add a ring to an aromatic ring starting with a cyclic anhydride
 Note that the Clemmensen reagents do not reduce the carboxylic acid
17 18


The nature of groups already on an aromatic ring affect both the reactivity and orientation of future substitution
 Activating groups cause the aromatic ring to be more reactive than benzene
 Deactivating groups cause the aromatic ring to be less reactive than benzene
 Ortho-para directors direct future substitution to the ortho and para positions
 Meta directors direct future substitution to the meta position
 Activating Groups : Ortho-Para Directors

All activating groups are also ortho-para directors
 The halides are also ortho-para directors but are mildly deactivating
 Th
 th l f t l i th di t
Toluene reacts more readily than benzene, e.g. at a lower temperatures than benzene
19
 The methyl group of toluene is an ortho-para director
 Amino and hydroxyl groups are also activating and ortho-para directors

Alkyl groups and heteroatoms with one or more unshared electron pairs directly bonded to the aromatic ring will be ortho-para directors (see chart later)
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 Deactivating Groups : Meta Directors
 Strong electron-withdrawing groups such as nitro, carboxyl, and sulfonate are deactivators and meta directors
 Halo Substitutents: Deactivating Ortho-Para Direct ors

Chloro and bromo groups are weakly deactivating but are also ortho, para directors
 In electrophilic substitution of chlorobenzene, the ortho and para products are major:
21

Chapter 15 22
 Theory of Substituent Effects on Electrophilic Substitution
 Reactivity : The Effect of Electron-Releasing and Electron-
Withdrawing Groups

Electron-releasing groups Q activate the ring toward further reaction
 Electron-releasing groups stabilize the transition state of the first step of substitution and lead to lower

G ‡ and faster rates of reaction
 Electron-withdrawing groups Q deactivate the ring toward further reaction
 Electron-withdrawing groups destabilize the transition state and lead to higher

G ‡ slower rates of reaction and
 The following free-energy profiles compare the stability of the first transition state in electrophilic substitution when various types of substitutents are already on the ring
 These substitutents are electron-withdrawing, neutral (e.g., H), and electrondonating
23 Chapter 15 24
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 Inductive and Resonance Effects: Theory of Orientation

The inductive effect of some substituent Q arises from the interaction of the polarized bond to Q with the developing positive charge in the ring as an electrophile reacts with it
 If Q is an electron-withdrawing group then attack on the ring is slowed because this leads to additional positive charge on the ring
 The following are some other groups that have an electronhas a partial or full positive charge
25
 The resonance effect of Q refers to its ability to increase or decrease the resonance stabilization of the arenium ion
 When Q has a lone pair on the atom directly attached to the ring it can stabilize the arenium by contributing a fourth resonance form
 Electron-donating resonance ability is summarized below
26
 Meta-directing Groups: Mechanism of EAS
 All meta-directing groups have either a partial or full positive charge on the atom directly attached to the aromatic ring
 The trifluoromethyl group destabilizes the arenium ion intermediate in ortho and para substitution pathways
 The arenium ion resulting from meta substitution is not so destabilized and therefore meta substitution is favored
 Ortho-Para Directing Groups

Many ortho-para directors are groups that have a lone pair of electrons on the atom directly attached to the ring
27 28
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
Activating groups having unshared electrons on the atom bonded to the ring exert primarily a resonance effect
 The aromatic ring is activated because of the resonance effect of these groups
 They are ortho-para directors because they contribute a fourth important resonance form which stabilizes the arenium ion in the cases of ortho and para substitution only
 The fourth resonance form that involves the heteroatom is particularly important because the octet rule is satisfied for all atoms in the arenium ion
 Halo groups are ortho-para directors but are also deactivating (!)


The electron-withdrawing inductive effect of the halide is the primary influence that deactivates haloaromatic compounds toward electrophilic aromatic substitution
The electron-donating resonance effect of the halogen’s unshared electron pairs is the primary ortho-para directing influence
29 30
 Ortho-Para Direction and Reactivity of Alkylbenzenes
 Alkyl groups activate aromatic rings by inductively stabilizing the transition state leading to the arenium ion
 Alkyl groups are ortho-para directors because they inductively stabilize one of the resonance forms of the arenium ion in ortho and para substitution
31

 Benzylic Radicals and Cations
 When toluene undergoes hydrogen abstraction from its methyl group it produces a benzyl radical
 A benzylic radical is a radical in which the carbon bearing the unpaired electron is directly bonded to an aromatic ring
 Departure of a leaving group by an S
N
1 process from a benzylic position leads to formation of a benzylic cation
32
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Benzylic radicals and cations are stabilized by resonance delocalization of the radical and positive charge, respectively
33
 Halogenation of the Side Chain: Benzylic Radicals

Benzylic halogenation takes place under conditions which favor radical reactions

Reaction of N-bromosuccinamide with toluene in the presence of light leads to allylic bromination
 Recall N-bromosuccinamide produces a low concentration of bromine which favors radical reaction
 Reaction of toluene with excess chlorine can produce multiple benzylic chlorinations
34
Step by step mechanism of benzylic halogenation
 When ethylbenzene or propylbenzene react under radical conditions, halogenation occurs primarily at the benzylic position
35
 Stability of Conjugated Alkenylbenzenes

Conjugated alkenyl benzenes are more stable than nonconjugated alkenylbenzenes
 Dehydration of the alcohol below yields only the more stable conjugated alkenyl benzene
 Additions proceed through the most stable benzylic radical or benzylic cation intermediates
36
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 Oxidation of the Side Chain
Alkyl and unsaturated side chains of aromatic rings can be oxidized to the carboxylic acid using hot KMnO
4

 When designing a synthesis of substituted benzenes, the order in which the substituents are introduced is crucial
 Example: Synthesize ortho-, meta-, and para-nitrobenzoic acid from toluene
37 38
 Use of Protecting and Blocking Groups

Strong activating groups such as amino and hydroxyl cause the aromatic ring to be so reactive that unwanted reactions can take place
 These groups activate aromatic rings to oxidation by nitric acid when nitration is attempted; the ring is destroyed
 An amino group can be protected (and turned into a moderately activating group) by acetylation
 Example: The synthesis of p- and o-nitroaniline from aniline
 A sulfonic acid group is used as a blocking group to force ortho substitution
Chapter 15 39 40
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 Orientation in Disubstituted Benzen es

When two substituents are present on the ring initially, the more powerful activating group generally determines the orientation of subsequent substitution
 Ortho-para directors determine orientation over meta directors
 Substitution does not occur between meta substituents due to steric hindrance

 Allylic and benzylic halides are classified in similar fashion to other halides
41 42
 Both primary and secondary allylic and benzylic halides can undergo S
N
1 or S
N
2 reaction
 These primary halides are able to undergo S
N
1 reaction because of the added stability of the allylic and benzylic carbocation

Tertiary allylic and benzylic halides can only undergo S
N
1 reaction
Chapter 15 43
benzene
H
2
/Ni slow
+ cyclohexadienes
H
2
/Ni fast cyclohexene
H
2
/Ni fast benzene cyclohexane
The Birch reduction
Na
NH
3
, EtOH
1,4-cyclohexadiene
44
11